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Although mast cells have long been known, they are not yet fully understood. They are traditionally recognized for their role in allergic reactions through the IgE/FcεRI axis, but different groups of surface receptors have since been characterized, which appear to be involved in the manifestation of peculiar clinical features. In particular, MRGPRX2 has emerged as a crucial receptor involved in degranulating human skin mast cells. Because of mast cells’ close proximity to peripheral nerve endings, it may play a key role in neuroimmune interactions. This paper provides an overview of mast cell contributions to hypersensitivity and so-called “pseudoallergic” reactions, as well as an update on neuroinflammatory implications in the main models of airway and skin allergic diseases. In particular, the main cellular characteristics and the most relevant surface receptors involved in MC pathophysiology have been reappraised in light of recent advancements in MC research. Molecular and clinical aspects related to MC degranulation induced by IgE or MRGPRX2 have been analyzed and compared, along with their possible repercussions and limitations on future therapeutic perspectives.

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections . The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization , but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.

The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and calcitonin gene-related protein (CGRP), are produced by sensory nerves in the dermis; they induce mast cells to release vasoactive amines that facilitate infiltration of neutrophils and T cells. Some receptors are more important than others in the generation of itch. The Mas-related G protein-coupled receptors (Mrgpr) family as well as transient receptor potential ankyrin 1 (TRPA1) and protease activated receptor 2(Par2) have important roles in itch and inflammation. The activation of MrgprX1 degranulates mast cells to communicate with sensory nerve and cutaneous cells for developing neurogenic inflammation. Mrgprs and transient receptor potential vanilloid 4 (TRPV4) are crucial for the generation of skin diseases like rosacea, while SP, CGRP, somatostatin, β-endorphin, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) can modulate the immune system during psoriasis development. The increased level of SP, in atopic dermatitis, induces the release of interferon (IFN)-γ, interleukin (IL)-4, tumor necrosis factor (TNF)-α, and IL-10 from the peripheral blood mononuclear leukocytes. We are finally starting to understand the intricate connections between the skin neurons and resident skin cells and how their interaction can be key to controlling inflammation and from there the pathogenesis of diseases like atopic dermatitis, psoriasis, and rosacea.

Pain has been considered as a concept of sensation that we feel as a reaction to the stimulus of our surrounding, putting us in harm’s way and acting as a form of defense mechanism that our body has permanently installed into its system. However, pain leads to a huge chunk of finances within the healthcare system with continuous rehabilitation of patients with adverse pain sensations, which might reduce not only their quality of life but also their productivity at work setting back the pace of our economy. It may not look like a huge deal but factor in pain as an issue for majority of us, it becomes an economical burden. Although pain has been researched into and understood by numerous researches, from its definition, mechanism of action to its inhibition in hopes of finding an absolute solution for victims of pain, the pathways of pain sensation, neurotransmitters involved in producing such a sensation are not comprehensively reviewed. Therefore, this review article aims to put in place a thorough understanding of major pain conditions that we experience—nociceptive, inflammatory and physiologically dysfunction, such as neuropathic pain and its modulation and feedback systems. Moreover, the complete mechanism of conduction is compiled within this article, elucidating understandings from various researches and breakthroughs.

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.

Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre-clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury.

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Inflammation is the body’s response to injury and infection, involving a complex biological response of the somatosensory, immune, autonomic, and vascular systems. Inflammatory mediators such as prostaglandin, proinflammatory cytokines, and chemokines induce pain via direct activation of nociceptors, the primary sensory neurons that detect noxious stimuli. Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release and rapid plasma extravasation and edema, contributing to pain conditions such as headache. Neuroinflammation is a localized inflammation in the peripheral nervous system (PNS) and central nervous system (CNS). A characteristic feature of neuroinflammation is the activation of glial cells in dorsal root ganglia, spinal cord, and brain which leads to the production of proinflammatory cytokines and chemokines in the PNS and CNS that drives peripheral sensitization and central sensitization. Here, we discuss the distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the regulation of different types of pain conditions, with a special focus on neuroinflammation in postoperative pain and opioid-induced hyperalgesia.

The etiology of migraine pain involves sensitized meningeal afferents that densely innervate the dural vasculature. These afferents, with their cell bodies located in the trigeminal ganglion, project to the nucleus caudalis, which in turn transmits signals to higher brain centers. Factors such as chronic stress, diet, hormonal fluctuations, or events like cortical spreading depression can generate a state of “sterile inflammation” in the intracranial meninges resulting in the sensitization and activation of trigeminal meningeal nociceptors. This sterile inflammatory phenotype also referred to as neurogenic inflammation is characterized by the release of neuropeptides (such as substance P, calcitonin gene related peptide) from the trigeminal innervation. This release leads to vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Although neurogenic inflammation has been observed and extensively studied in peripheral tissues, its role has been primarily investigated in the genesis and maintenance of migraine pain. While some aspects of neurogenic inflammation has been disregarded in the occurrence of migraine pain, targeted analysis of factors have opened up the possibilities of a dialogue between the neurons and immune cells in driving such a sterile neuroinflammatory state in migraine pathophysiology.

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization. As such, fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems. This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.